Method of embryo transfer that eliminates transferred air while hormonally inducing implantation and apparatus

ABSTRACT

A method of embryo transfer (“ET”) that improves fertility rates by eliminating transferred air during the procedure is provided. Also provided is a method for hormonally enhancing the uterine wall of a patient either prior to or during the time of ET. Quantitative administration of transfer solutions is accomplished with a modified apparatus that provides for implantation of an embryo into the uterus of a patient. The apparatus comprises an outer sheath and an inner lumen arranged to be slidably disposed within the outer sheath. The inner lumen includes at least one visual marker situated on the exterior surface adjacent its distal end thereof.

RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.12/348,571, filed Jan. 5, 2009, which claims the benefit of priority toU.S. Provisional Application No. 61/188,021, filed Aug. 6, 2008, whichapplications are hereby incorporated by reference in their entireties.

FIELD OF THE INVENTION

This invention relates to a minimally-invasive medical procedure ofembryo transfer utilizing a uterine transfer catheter that depositsfertilized eggs into the uterus whereby implantation of an embryooccurs.

BACKGROUND OF THE INVENTION

Human in vitro fertilization (IVF) and embryo transfer (ET) was firstsuccessfully performed in 1978 and has since been widely practiced totreat infertile couples who have failed with other conventional methods.The IVF/ET procedure typically involves hormonal stimulation of thefemale to initially suppress her natural ovulation, and then stimulatedevelopment of ovarian follicles with fertility drugs. The mature eggsare harvested from the ovary using a needle and then sorted by maturityand egg quality. Preferred eggs are then mixed with sperm from the maleto be fertilized. After some time, the embryo(s) mature and aretransferred, along with a volume of fluid, to the uterus using adelivery catheter. The delivery catheter is made of soft plasticmaterial to avoid damage to the endometrium of the uterus. The deliverycatheter is guided through the cervix to the uterus by a physician wherethe loaded embryos within the fluid is deposited, completing the ET.

One method of catheter loading is referred to as “the transfer bubblemethod” and has been universally accepted by professionals and has beenin place over four decades. The catheter is loaded with a series ofalternate air and transfer liquid (e.g., saline, P-1 or glycerine) involumes approximating 3 microliters. Volumes of air separate thetransfer liquid to keep the embryos contained within the fluid and alsoto ease visualization of the components. Upon ejection of the fluids,about 100 microliters of air is also ejected with the quantity of mediumand transfer liquid containing the embryos. Generally, there are a totalof approximately 6 microliters of fluid and 100 microliters of airdeposited at the ejection site in the uterus. These volumes can varygreatly depending on specific hospital protocol and there has beenresearch done to study the effects of varying medium volumes uponpregnancy rates. Some studies demonstrate that a transferred volume ofless than 50 microliters is optimal for successful ET whereby otherstudies show that widely varying transfer volumes of medium have littleeffect on the outcome of IVF procedures.

Studies also have found that the transferred air within the uterus cansometimes act as a barrier that prohibits movement of the embryos fromthe site of ejection to the optimal location for implantation within theuterus. This air bubble creates an area of surface tension to which theembryos may adhere and remain positioned, prohibiting interaction of theembryo with the receptive surface of the uterus. Moreover, under thetransfer bubble method, latent embryos can attach themselves to theinternal walls of the catheter requiring further manipulation of theembryos and thereby decreasing the likelihood of successful ET.

While improvements in the techniques and instrumentation used in thisprocedure have provided significant increases in pregnancy rates andbirths, the overall numbers remain fairly low, around 25%. There areseveral factors that impact on IVF success including the design of thedelivery catheter. Ultrasound guided catheters have been included in ETprocedures to aid visualization of the tip and facilitate optimizedembryo deposition at the prime location within the uterus.

In addition, the high cost of the IVF procedure combined with this lowprobability of success compels couples to deliver multiple embryos toincrease the chance of at least one successful implantation. Often,unwanted multiple births result and jeopardize the health of motherand/or children, which has recently raised questions concerning themedical ethics of such practice. If a higher pregnancy rate could beachieved, the need for multiple embryo delivery would be lessened orpossibly eliminated.

With the high cost of IVF and contrastingly low pregnancy rate, what isneeded is a method of ET that reduces the quantity of air that istypically transferred to the uterus along with the embryos in medium.The conventional method of catheter loading referred to as “the transferbubble method” that deposits these relatively large volumes of air hasbeen taught worldwide and universally accepted by professionals in theIVF field. Even as studies demonstrate the difficulties associated withthis large transferred air bubble, this method is the only one used. Animproved method of ET that eliminates any volume of transferred air willundoubtedly improve the probability of successful embryo implantationand increase pregnancy rates overall.

SUMMARY OF THE INVENTION

A method of embryo transfer (“ET”) that improves fertility rates byeliminating transferred air during the procedure is provided. Alsoprovided is a method for hormonally enhancing the uterine wall of apatient at the time of ET.

Direct administration of hormones into the uterus may be achieved byincluding the hormones in the milieu of solutions utilized during thetransfer of one or more embryos into the endometrium during ET. Lutealsupport is maintained by slow dissolution of the deposited hormones bydirect injection into the uterus, as opposed to introducing the hormonessystemically. Further direct administration allows for optimizing thedelivery time of these hormones in the preparation of the uterus priorto or simultaneously with the delivery of a fertilized egg at the siteof implantation.

The present invention embodies a method of targeted intrauterineadministration in a timed sequence of events to precisely establish aprogesterone dominant uterus that is primed and ready to receive adeveloping blastocyst for implantation

Quantitative administration of the hormonal solutions is accomplished bya modified delivery catheter that comprises an outer sheath having aproximal end and a distal end. An inner lumen is arranged to be slidablydisposed within the outer sheath. The inner lumen includes a proximalend, a distal end, and a passageway therethrough. The inner lumenincludes at least one visual marker situated on the exterior surfaceadjacent its distal end thereof to enable accurate volumes of fluidmedia in which one or more embryos are situated to be drawn into thedeliver catheter.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an elevational view of an embodiment of the delivery catheterof the present invention with a syringe shown attached at the proximalend thereof, the syringe including a barrel and a plunger disposedtherein.

FIG. 2 is a cross-sectional view taken along line 2-2 of FIG. 1.

FIG. 3 is a cross-sectional view taken along line 3-3 of FIG. 1.

FIG. 4 is a cross-sectional view of a portion of an embodiment of thedelivery catheter of the present invention wherein the inner lumen isillustrated as retaining therein a first portion comprised of a washfluid, a second portion comprised of an oil, and a third portioncomprised of one or more embryos disposed within a fluid culture medium.

FIG. 5 is a cross-section view of a portion of an embodiment of thedelivery catheter of the present invention wherein the inner lumen isillustrated as retaining therein a first portion comprised of a washfluid, a second portion comprised of an oil, and a third portioncomprised of one or more embryos disposed within a fluid culture medium.

FIG. 6 is a front end view of the delivery catheter of the presentinvention.

FIG. 7 is an illustration of several embryos implanted on the wall of auterus after an embryo transfer procedure has been conducted.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The problems associated with large quantities of transferred air duringET procedures are solved and a technical advance is achieved in animproved delivery catheter for use in an ET procedure and method forloading the delivery catheter that involves replacing the air bubblewith a liquid medium, e.g., a separation oil, at the start of theprocedure, to improve the rate of fertility.

Referring now in detail to the various figures of the drawings whereinlike reference characters refer to like parts, there is shown at 6 inFIGS. 1 through 6, an embodiment of the delivery catheter is illustratedas including an outer sheath 10 being in the form of a hollow tube andprovided towards its proximal end with a hub 20 provided with a seriesof axially extending fins 24 to assist in manipulation. As best shown inFIG. 5, the distal end of the outer sheath 10 is provided at intervalsof a predetermined distance, e.g., one centimeter, with gradations 28 ofany suitable measure, e.g., microliters. The gradations are marked as aplurality of rings about the distal end, and which may be slightlyindented into the outer surface thereof. Alternatively, the gradations28 may be of a distinctive color. As best seen in FIGS. 5 and 6, theremote distal tip 32 of the outer sheath 10 is chamfered for minimaltrauma. The outer sheath 10 is formed of any suitable material, andpreferably a generally rigid plastic material such as TEFLON®.

The outer sheath 10 is adapted to accommodate therewithin an inner lumen36 having an external diameter such as to be an easy sliding fit withinthe outer sheath 10 and an internal passageway 34 having a diameter of asize to readily accommodate an embryo. As best shown in FIGS. 1 and 5,the inner lumen 36 is provided at its proximal end with a hub 40, thehub 40 being provided about its external surface with a plurality ofaxially extending fins 44 to assist manipulation. The inner lumen 36 isprovided with an inner bore 42 (FIG. 2) that is in open communicationwith the internal passageway 34. The hubs 20 and 40 are adapted suchthat they interlock in their closed position as shown in FIGS. 1 and 5.The hubs 20 and 40 are provided to enable a physician and/or anembryologist to hold the outer sheath 10 with one hand while using theother hand to slide the inner lumen 36 through the outer sheath 10during an embryo transfer procedure.

Referring now to FIGS. 1 and 5, the distal end of the inner lumen 36 isprovided at intervals of a predetermined distance, e.g., one centimeter,with gradations 38 of any suitable measure, e.g., microliters. Thegradations 38 are marked as a plurality of rings about the distal end,and may be slightly indented into the outer surface thereof.Alternatively, the gradations 38 may be of a distinctive color to allowthe operator to precisely aspirate an exact quantity of a fluid mediumto achieve a consistent protocol. As best shown in FIGS. 2-5, the remotedistal tip 46 of the inner lumen 36 is provided with a smoothly radiusedchamfer for minimal trauma to the uterine tissues. The inner lumen 36 inaccordance with this embodiment of the invention is preferably soft andflexible and formed of a biologically acceptable synthetic polymer.

Referring now to FIGS. 1-4, there is shown a standard syringe 52 havinga barrel 56 and a plunger 60 disposed therein. Referring now to FIG. 1,the syringe 52 is shown with the plunger 60 disposed fully within thelength of the barrel 56. The syringe 52 includes a distal end 61 whichis sized to snugly fit within the inner bore 42 of the inner lumen 36.

Referring now to FIGS. 2-4, to load the inner lumen 36 for the embryotransfer procedure, the distal end 61 of the syringe 52 is inserted intothe inner bore 42 of the inner lumen 36 with the plunger 60 disposedfully within the length of the barrel 56 of the syringe 52. Apredetermined amount of a first fluid medium, e.g., from 6 to 9microliters of a wash fluid 64, is drawn into the internal passageway 34of the inner lumen 36 and into the barrel 56 of the syringe 52 bywithdrawing the plunger 60 along a portion of the length of the barrel56. Next, an excess amount of the wash fluid 64 is ejected from thesyringe 52 and internal passageway 34 by depressing the plunger 60. Byutilizing the gradations 38 marked on the distal end of the inner lumen36, an accurate volume of wash fluid 64 can be obtained within theinternal passageway 34. The ET delivery catheter 6 is then heldvertically to enable air to escape out the remote distal tip 46 of theinner lumen 36. Often, the sides of the ET delivery catheter 6 aretapped by the forefingers to loosen any air bubbles from the internalsides of the barrel 56.

Referring now to FIG. 3, a predetermined amount of a second fluidmedium, e.g., approximately 3 microliters of a separation oil 68, may bedrawn into the internal passageway 34 of the inner lumen 36 adjacent thefirst fluid medium, by slowly withdrawing the plunger 60 from the barrel56 of the syringe 52, as indicated by the arrow in FIG. 3. Any suitableseparation oil 68 may be utilized for the purpose of separating the washfluid 64 from the culture medium containing one or more embryos 72. Oneparticular product which could be utilized as a separation oil inaccordance with the present invention is an enhanced oil for tissueculture manufactured by Conception Technologies of San Diego, Calif.under catalog numbers OTC-100 (100 mL) and OTC-500 (500 mL). Byutilizing the gradations 38 marked on the distal end of the inner lumen36, an accurate volume of the separation oil 68 within the internalpassageway 34 can be achieved. Likewise, unwanted air and any unneededvolume of separation oil 68 can be expelled through the remote distaltip 46 by depressing the plunger 60 of the syringe 52 and/or tappingwith forefingers to loosen air bubbles.

Lastly, as best shown in FIG. 4, the gradations 38 located at the distalend of the inner lumen 36 enable an operator to draw a predeterminedamount of a third fluid medium, e.g., approximately 3-6 microliters of afluid culture medium containing one or more embryos 72, into theinternal passageway 34 of the inner lumen 36. As shown in FIG. 4, thethird fluid medium in which the embryos 72 are located is shown as beingsituated adjacent the separation oil 68. The fluid culture medium inwhich the embryos 72 are located includes a water-based portion andsometimes, an oil-based portion. When an oil-based portion is used, itis done so to prevent evaporation of the water-based portion and preventdehydration of the embryos 72. One product which is suitable forutilizing as the oil-based portion of the fluid culture medium is theenhanced oil for tissue culture manufactured by Conception Technologiesof San Diego, Calif. under catalog numbers OTC-100 (100 mL) and OTC-500(500 mL), as mentioned in connection with the separation oil describedabove.

As best shown in FIG. 4, the three fluid media, e.g., the wash fluid 64,the separation oil 68, and the plurality of embryos 72 disposed within afluid culture medium are shown disposed within the internal passageway34 of the inner lumen 36. The separation oil 68 is utilized as areplacement to the volume of air which under existing techniques isutilized to separate the wash fluid 64 from the embryos 72. By replacingthe volume of air with the separation oil 68, the drawbacks associatedwith the use of air in embryo transfer procedures is eliminated. Forexample, the use of a separation oil 68 will facilitate movement of theembryos 72 from the site of ejection to the optimal location forimplantation within the uterus and will facilitate interaction betweenthe embryo 72 and the receptive surface of the uterus. Embryos 72 willflow more readily within a liquid environment than a gaseous (air)environment.

In accordance with the present invention, ingredients may be added tothe separation oil 68 and/or wash fluid 64, including progesteroneand/or estrogen to stimulate the luteal phase which determines the timeof ovulation within the menstrual cycle and establishes the peak momentof receptivity within the uterus. By including such hormones within theseparation oil 68 and wash fluid 64 for administration into the uterus,the concentrations of such hormones needed for luteal stimulation andsupport is substantially less than required when such hormones areadministered by vaginal suppository, intramuscular or other systemicmeans.

It should be understood that the hormones needed for stimulation of theluteal phase may be added to the separation oil 68 and/or the wash fluid64 and delivered directly into the uterus during an ET procedureutilizing the delivery catheter 6 described herein. Alternatively, thehormones may be introduced directly into the uterus utilizing any othersuitable delivery device and may be delivered into the uterus at anypoint in time, either prior to or during the ET procedure.

One embodiment of the present invention is a method to hormonallyprepare the uterus prior to the introduction of a fertilized egg duringembryonic implantation. Embryonic Implantation in humans is a complexprocess, part of which requires hormonal preparation of the uterus priorto the involvement of a fertilized egg. This preparation has beendescribed in general terms as “the window of implantation” of theovulation cycle whereby progesterone is secreted by the corpus luteum,situated on the developing ovary, and travels down the fallopian tubeinto the uterus in a slow but timely manner each month of a woman'shormonal cycle. Consequently, embryonic implantation is a synchronizedprocess between hormonal preparation and implantation of a fertilizedegg.

Generally about 15% of the population experience difficulty in achievingpregnancy by the natural process involving hormonal preparation andimplantation so many revert to an assisted or artificial means ofachieving pregnancy such as in vitro fertilization. For in vitrofertilization to occur, the same uterine hormonal preparation during thewindow of implantation, as in a natural pregnancy, must be achieved inorder for successful implantation of a deposited embryo and ultimatepregnancy.

Current approaches to methods involving uterine preparation includeintramuscular injection (IM) of micronized progesterone in oil andperi-vaginal delivery (PV) of an assortment of products that containmicronized progesterone such as: gels, effervescent tablets, creams,suppositories, etc. These forms of hormonal delivery enter thebloodstream and the progesterone molecules eventually reach the outsideof the uterus (myometrium) and propagate toward the endometrialinnermost layer of the uterus, where implantation occurs.

Unfortunately, these conventional “extra-uterine” systemicadministrations of progesterone result in inconsistent bioavailability,especially with respect to timing and the window of implantation whichaffects proper and consistent embryonic implantation. Evidence supportedby endometrial biopsies demonstrate periods of time when progesteroneconcentrations are far below the levels known to facilitateimplantation. Conversely, some endometrial biopsies show excessivelyhigh progesterone concentration levels, far outside the norm, which actas a deterrent to implantation, much like an intrauterine device (IUD)that emits daily high doses of progesterone to prohibit implantation andpregnancy.

One embodiment of the present invention provides a means to control thebioavailability of progesterone within an acceptable concentration andtime range in order to establish a progesterone dominant uterus (overantagonist-estrogen) and achieve implantation (and ultimately pregnancy)more often than the 27% fertility plateau that is witnessed in IVF whenone single embryo is transferred to the uterus,

Another embodiment of the invention provides a method of targetedintrauterine administration to precisely establish a progesteronedominant uterus within the window of implantation, resulting in a uterusprimed and ready to receive a developing blastocyst for implantation.This targeted approach mitigates the anatomical and physiologicalaspects found in prior methods that restrict progesterone reaching theendometrium, while eliminating the excessive buildup that occurs whichhinders implantation via conventional methods.

Accordingly, a hormonal preparation containing a formulation with atleast one implantation promoter such as progesterone, estrogen orcombinations thereof is delivered to the target site. The hormonalpreparation is administered in the proper proportions and with theproper timing to optimize and ensure the probability of a successfulpregnancy. The time period for administration of a hormonal preparationprior to depositing the embryo varies from the same day to 270 days postadministration. The concentration range of the implantation promoter isbetween approximately 0.001 micrograms to 1000 milligrams. Hormonalpreparations may be in a nanoformulation and incorporate a micronizedparticle mix using micronization methods known in the art such aswet-milling of particles. Excipients can be used which are known toalter the pharmacokinetics and dynamics of hormonal bioavailability.

The optimum specific time period and hormone concentration range can bedetermined through routine experimentation wherein the most desirablebioavailability range for promoting the maximum effect of uterinefactors necessary for implantation is determined. Because of the directdelivery to the endometrial surface at precisely the right time, timingand concentration can be easily modified for optimum activity of theuterine factors. These factors include; Aquaporins (AQPs), EpithelialSodium Channels (ENaCs), Prostaglandins, Activation of the Sodium Pumpand HNE-1 Protein for embryonic transport and immobilization, and othergenomic factors on the uterine and blastocyst surfaces that requireprecise hormonal exposure to assure needed dialog between the uterus andblastocyst (termed: maternal dialog), for the continued decidualizationprocess of implantation to occur.

A still further embodiment of the present invention is where theadministration of an implantation promoter to the uterine target siteoccurs simultaneously with the deposition of the embryo. Administrationand deposition occur simultaneously through the same delivery device.

Depositing the fertilized embryo at the implantation site can occurthrough any delivery means know in the art. These may include an embryotransfer catheter, syringe, or other ejection device. The fertilizedembryo can also be deposited directly by manually placement of theembryo.

However another embodiment of the present invention incorporates the useof a delivery means having a catheter with an outer sheath and an innerlumen slidably disposed within the outer sheath, as described elsewhereherein, the internal lumen has an internal passageway configured to holdan embryo and having a means for quantitative administration of a fluidmedium. Accordingly both the embryo and hormonal preparation can bedelivered through the same device with the quantitative administrationof a fluid medium containing a hormonal preparation having a formulationwith at least one implantation promoter. This delivery means is ideallysuited for the simultaneous delivery of a hormone preparation and thedeposition of the fertilized embryo. Also because of the quantitativedelivery of the device, deposition of the fertilized embryo can occurwith the precisely-timed delivery of a prior amount of implantationpromoter to have the uterus hormonally prepared for implantation.

Referring now to FIGS. 5 and 7, once the predetermined volumes of fluidmedia have been accurately drawn within the internal passageway 34 ofthe inner lumen 36, delivery of the embryos 72 to the uterus 76 ispossible. The distal ends of the outer sheath 10 and inner lumen 36 arebrought together. The physician and/or embryologist directs the end ofthe ET delivery catheter 6 transvaginally to the desired location withinthe uterus, either by conventional means or by improved ultrasoundguided techniques. The gradations 28 provided at the distal end of theouter sheath 10 enable the physician and/or the embryologist todetermine the distance the catheter 6 has been inserted into the uterus.The ET delivery catheter 6 must be gently advanced through the cervicalcanal to overcome obstruction or tortuous route so that the deliverycatheter 6 can pass into the uterus.

The physician and/or embryologist then ejects the embryos 72 through thedistal end of the inner lumen 36 by depressing the plunger 60 of thesyringe 52. In this manner, the entire contents are expelled out of theinternal passageway 34. In this manner, the wash fluid 64 washes thewall of the internal passageway 34 and carries out any adherent embryos72 that may have attached themselves to the wall of the internalpassageway 34 by way of surface tension. Once the embryo transfer iscompleted, the physician extracts the distal tip of the ET deliverycatheter from the cervix. This method of ET is superior to other methodsbecause the delivered embryos are much more likely to flow within aliquid environment than a gaseous (air) environment.

The details of the construction or composition of the various elementsof the ET delivery catheter 6 of the present invention not otherwisedisclosed are not believed to be critical to the achievement of theadvantages of the present invention, so long as the elements possess thestrength or flexibility or softness needed for them to perform asdisclosed. The details of such construction is believed to be wellwithin the ability of one of ordinary skill in this area, in view of thepresent disclosure, and are within the spirit of the invention and thescope of the claims.

The invention claimed is:
 1. A method for artificial embryonicimplantation in a uterine wall of a female subject comprising: a.directly administering at least one implantation promoter in ananoformulation sufficient to promote an activation of uterine factorsat a target site on the uterine wall within a window of implantation;and b. depositing a fertilized embryo at a prepared site whereinadministering the implantation promoter and depositing a fertilizedembryo are through a distal end of an inner lumen for an embryo transferdelivery catheter to locally target a portion of the uterine wall. 2.The method of claim 1 wherein the female subject is human.
 3. The methodof claim 1 wherein the implantation promoter is selected from a groupconsisting of known amounts of progesterone, estrogen, and a combinationthereof.
 4. The method of claim 1 wherein the implantation promoter isprogesterone.
 5. The method of claim 1 wherein a concentration of theimplantation promoter is between approximately 0.001 micrograms to 1000milligrams administered at the target site.
 6. The method of claim 1wherein the uterine factors are selected from the group consisting ofaquaporins, epithelial sodium channels, prostaglandins, activation of asodium pump, HNE-1 protein and combinations thereof.
 7. The method ofclaim 1 wherein the window of implantation is a time period for having amaximum effect on the uterine factors as determined at the target sitefor an individual female subject.
 8. The method of claim 1 wherein thewindow of implantation is between approximately a day of depositing afertilized embryo to approximately 270 days prior to depositing afertilized embryo.
 9. The method of claim 1 wherein administering theimplantation promoter through the embryo transfer delivery catheter isprior to the delivery of the fertilized embryo.